Heart failure afflicts more than two million Americans, and congestive heart failure is recognized as the most common cause of hospitalization and mortality in Western society. Congestive heart failure is a syndrome characterized by left ventricular dysfunction, reduced exercise tolerance, impaired quality of life and dramatically shortened life expectancy. Decreased contractility of the left ventricle leads to reduced cardiac output with consequent systemic arterial and venous vasoconstriction.
Contractility appears to be regulated primarily by calcium flow. For the heart to contract, calcium must be released into the main body (sarcoplasm) of cardiac cells. The more calcium that flows in, the stronger the force of contraction. When the heart relaxes, calcium is pumped out of the sarcoplasm into the sarcoplasmic reticulum (SR). Thus, the heart muscle is triggered to contract and relax by a mechanism in which calcium (Ca2+) is released from a reservoir into the muscle cell, or myocyte, and then rapidly pumped back into the reservoir, called the sarcoplasmic reticulum (SR) by the Sarco(endo)plasmic reticulum Ca2+-ATPase 2a (SERCA2a).
The efficiency with which Ca2+ is returned to SR determines the amount of Ca2+ that is available for the next contraction. Phospholamban (PLN) is a regulatory phosphoprotein that modulates the active transport of Ca2+ by the cardiac sarcoplasmic reticular Ca(2+)-ATPase enzyme (SERCA2) into the lumen of the sarcoplasmic reticulum. Phospholamban, which is a reversible inhibitor of SERCA2, represses the enzyme's activity, and this inhibition is relieved upon phosphorylation of PLN in response to β-adrenergic stimulation.
The ratio of phospholamban to SERCA2 appears to be critical in regulating myocardial contractility, and alterations in this ratio may contribute to the functional deterioration observed during heart failure. (Koss et al. (1997) Basic Res Cardiol. 1997;92 Suppl 1:17-24). In particular, a decreased SERCA2a/PLN ratio, which is commonly observed in heart failure, leads to reduced SR Ca2+ reserve and weakened contractility. The importance of the SERCA2a:PLN ratio to contractility has also been examined using PLN knockout mice; murine heart failure models (e.g., models that overexpress SERCA2a, as well as in isolated human cardiomyocytes (e.g., antisense-mediated PLN inhibition in myocytes that overexpress SERCA2a). See, e.g., MacLennan et al. (2003) Nat Rev Mol Cell Biol. 4(7):566-77; Eizema et al. (2000) Circulation 101(18):2193-9; del Monte et al. (2002) Circulation 105(8):904-7; Minamisawa et al. (1999) Cell 99(3):313-22.
However, modulation of PLN expression so as to modulate cardiac contractility has not been previously described. Furthermore, the ability to alter cardiac contractility by modulating PLN expression may have utility in treating and/or preventing congestive heart failure and/or other cardiac diseases.